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1.  Determination of Harmane and Harmine in Human Blood Using Reversed-Phased High-Performance Liquid Chromatography and Fluorescence Detection 
Analytical biochemistry  2000;279(2):125-129.
A number of tremorogenic β-carboline alkaloids have been found in common plant-derived foodstuffs, beverages, and inhaled substances. Because of their natural presence in the food chain, there is a growing concern regarding the potential risks of certain essen tial tremors associated with the long-term low-level dietary exposure to these alkaloids. The purpose of this study was to develop an effective analytical method to determine blood levels of two major β-car boline derivatives, harmane and harmine. Human blood was extracted with ethyl acetate and methyl-t-butyl ether (2:98) under an alkaline condition. After evaporation of organic solvent, the samples were re- constructed in methanol. The samples were fraction ated on a 250 × 4.6-mm C18 reversed-phase column with an isocratic mobile system consisting of 17.5 mM potassium phosphate buffer (ph 6.5) and methanol (30: 70), followed by an on-line fluorescence detection. The method had the detection limit to determine 206 and 81 pg/ml of harmane and harmine, respectively, in 10 ml of human blood. The intraday precision (C.V.) at 25 ng/ml was less than 6.7 and 3.4% for harmane and harmine, respectively. The interday precision was 7.3% for harmane and 5.4% for harmine. The method has proven sensitive, reproducible, and thus useful for both laboratory and clinical studies of β-carboline toxicities.
doi:10.1006/abio.1999.4456
PMCID: PMC4088954  PMID: 10706780
2.  Genome-wide association study identifies possible genetic risk factors for colorectal adenomas 
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown.
Methods
In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.
Results
No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81–0.94, p-value = 4.4×10−4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 OR = 1.32, 95% CI 1.18–1.47, p-value = 1.1×10−6).
Conclusions
This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies.
Impact
These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis.
doi:10.1158/1055-9965.EPI-12-1437
PMCID: PMC3716448  PMID: 23677573
Colorectal adenoma; genetic association
3.  New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women 
Background
Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations.
Methods
We evaluated nine of those non-replication loci in East Asians in order to identify new risk variants for breast cancer in these regions. First, we analyzed single nucleotide polymorphisms (SNPs) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (Stage 1). In each region we selected a SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (Stage 2). Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants.
Results
Two SNPs were replicated in Stage 2 at P < 0.05: rs1419026 at 6q14 (per allele OR = 1.07, 95% CI: 1.03-1.12, P = 3.0×10−4) and rs941827 at 10q25 (OR = 0.92, 95% CI: 0.89-0.96, P = 5.3×10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR = 0.88, 95% CI: 0.82-0.97, P = 5.3×10−5).
Conclusion
We identified a new breast cancer risk variant at 10q25 in East Asian women.
Impact
Results from this study improve the understanding of the genetic basis for breast cancer.
doi:10.1158/1055-9965.EPI-12-1393
PMCID: PMC3720126  PMID: 23677579
breast cancer; genetic susceptibility; GWAS replication; single nucleotide polymorphism
4.  Fish Intake and Risks of Total and Cause-specific Mortality in 2 Population-based Cohort Studies of 134,296 Men and Women 
American Journal of Epidemiology  2013;178(1):46-57.
Despite a proposed protective effect of fish intake on the risk of cardiovascular disease, epidemiologic evidence on fish intake and mortality is inconsistent. We investigated associations of fish intake, assessed through a validated food frequency questionnaire, with risks of total and cause-specific mortality in 2 prospective cohort studies of 134,296 Chinese men and women (1997–2009). Vital status and date and cause of death were ascertained through annual linkage to the Shanghai Vital Statistics Registry database and biennial home visits. Cox regression was used to calculate hazard ratios and corresponding 95% confidence intervals. After excluding the first year of observation, the analysis included 3,666 deaths among women and 2,170 deaths among men. Fish intake was inversely associated with risks of total, ischemic stroke, and diabetes mortality; the corresponding hazard ratios for the highest quintiles of intake compared with the lowest were 0.84 (95% confidence interval (CI): 0.76, 0.92), 0.63 (95% CI: 0.41, 0.94), and 0.61 (95% CI: 0.39, 0.95), respectively. No associations with cancer or ischemic heart disease mortality were observed. Further analyses suggested that the inverse associations with total, ischemic stroke, and diabetes mortality were primarily related to consumption of saltwater fish and intake of long-chain n-3 fatty acids. Overall, our findings support the postulated health benefits of fish consumption.
doi:10.1093/aje/kws584
PMCID: PMC3816343  PMID: 23788668
China; diet; fish intake; men; mortality; stroke; women
5.  Systematic Fine-Mapping of Association with BMI and Type 2 Diabetes at the FTO Locus by Integrating Results from Multiple Ethnic Groups 
PLoS ONE  2014;9(6):e101329.
Background/Objective
The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts.
Methods
The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison.
Results
We first examined the LD relationship between FTO SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target FTO region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations—Japanese, Vietnamese, Sri Lankan and Chinese (n≤26,109 for BMI association and n≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for FTO.
Conclusions
Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations—Europeans, Asians and Africans—are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.
doi:10.1371/journal.pone.0101329
PMCID: PMC4076329  PMID: 24978468
6.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825
7.  FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation 
Molecular Cancer  2014;13:150.
Background
Heat shock protein 90 (Hsp90) is a promising therapeutic target and inhibition of Hsp90 will presumably result in suppression of multiple signaling pathways. FW-04-806, a bis-oxazolyl macrolide compound extracted from China-native Streptomyces FIM-04-806, was reported to be identical in structure to the polyketide Conglobatin.
Methods
We adopted the methods of chemproteomics, computational docking, immunoprecipitation, siRNA gene knock down, Quantitative Real-time PCR and xenograft models on the research of FW-04-806 antitumor mechanism, through the HER2-overexpressing breast cancer SKBR3 and HER2-underexpressing breast cancer MCF-7 cell line.
Results
We have verified the direct binding of FW-04-806 to the N-terminal domain of Hsp90 and found that FW-04-806 inhibits Hsp90/cell division cycle protein 37 (Cdc37) chaperone/co-chaperone interactions, but does not affect ATP-binding capability of Hsp90, thereby leading to the degradation of multiple Hsp90 client proteins via the proteasome pathway. In breast cancer cell lines, FW-04-806 inhibits cell proliferation, caused G2/M cell cycle arrest, induced apoptosis, and downregulated Hsp90 client proteins HER2, Akt, Raf-1 and their phosphorylated forms (p-HER2, p-Akt) in a dose and time-dependent manner. Importantly, FW-04-806 displays a better anti-tumor effect in HER2-overexpressed SKBR3 tumor xenograft model than in HER2-underexpressed MCF-7 model. The result is consistent with cell proliferation assay and in vitro apoptosis assay applied for SKBR-3 and MCF-7. Furthermore, FW-04-806 has a favorable toxicity profile.
Conclusions
As a novel Hsp90 inhibitor, FW-04-806 binds to the N-terminal of Hsp90 and inhibits Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins. FW-04-806 displays promising antitumor activity against breast cancer cells both in vitro and in vivo, especially for HER2-overexpressed breast cancer cells.
doi:10.1186/1476-4598-13-150
PMCID: PMC4074137  PMID: 24927996
FW-04-806; Hsp90; Cdc37; HER2; Breast cancer
8.  dbCerEx: A Web-Based Database for the Analysis of Cervical Cancer Transcriptomes 
PLoS ONE  2014;9(6):e99834.
Background
Cervical cancers are ranked the second-most hazardous ailments among women worldwide. In the past two decades, microarray technologies have been applied to study genes involved in malignancy progress. However, in most of the published microarray studies, only a few genes were reported leaving rather a large amount of data unused. Also, RNA-Seq data has become more standard for transcriptome analysis and is widely applied in cancer studies. There is a growing demand for a tool to help the experimental researchers who are keen to explore cervical cancer gene therapy, but lack computer expertise to access and analyze the high throughput gene expression data.
Description
The dbCerEx database is designed to retrieve and process gene expression data from cervical cancer samples. It includes the genome wide expression profiles of cervical cancer samples, as well as a web utility to cluster genes with similar expression patterns. This feature will help researchers conduct further research to uncover novel gene functions.
Conclusion
The dbCerEx database is freely available for non-commercial use at http://128.135.207.10/dbCerEx/, and will be updated and integrated with more features as needed.
doi:10.1371/journal.pone.0099834
PMCID: PMC4053392  PMID: 24918550
9.  Collaborative Development of 2-Hydroxypropyl-β-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease 
In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Science (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community.
PMCID: PMC4048128  PMID: 24283970
2-hydroxypropyl-β-cyclodextrin; Niemann-Pick disease type C1; neurodegenerative rare disease; translational research
10.  T'ai Chi as Exercise Among Middle-Aged and Elderly Chinese in Urban China 
Abstract
Objectives
T'ai chi is a form of mind–body practice used as exercise in China, though limited data are available on characteristics of t'ai chi users and factors associated with practice.
Methods
Characteristics of and factors associated with t'ai chi practice among middle-aged and elder Chinese in Shanghai China were analyzed utilizing baseline data from the Shanghai Women's Health Study and Shanghai Men's Health Study. Logistic regression modeling was used to identify independent factors associated with the practice of t'ai chi among men and women.
Results
T'ai chi is the most common form of regular exercise in Shanghai China among middle-aged and elderly persons (22%), including among women (28%) and men (15%). Other popular forms of exercise were walking (7%), dancing (4%), and jogging (3%). A majority of adults who practiced t'ai chi used it as their exclusive type of exercise (69%). Overall, t'ai chi practitioners as compared to nonpractitioners were more likely women, older, more educated, retired versus still working, and more likely to report chronic medical conditions including pulmonary, gastrointestinal, and cardiovascular conditions. T'ai chi activity was associated with other health behaviors including nonsmoking, consuming ginseng, and participating in other forms of physical exercise.
Conclusions
T'ai chi is the predominant form of exercise among middle-aged and elderly Chinese in urban China, particularly among those with older age and chronic medical diseases. Future research is needed to see whether t'ai chi has similar or different benefits than conventional forms of exercise such as walking and jogging.
doi:10.1089/acm.2012.0223
PMCID: PMC3673590  PMID: 23289529
11.  Associations of leukocyte telomere length with body anthropometric indices and weight change in Chinese women 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20321.
Objective
Telomeres are specialized chromatin structures essential for maintenance of chromosomal integrity and stability. Obesity has been proposed to be associated with telomere shortening; however, epidemiologic evidence has been conflicting. We conducted a study to evaluate the associations of telomere length with various anthropometric indices of general and abdominal obesity, as well as weight change.
Design and Methods
The study included 2,912 Chinese women ages 40–70 years. Monochrome multiplex quantitative PCR was applied to measure relative telomere length. ANOVA and the Dunnett test were used to compare log-transformed relative telomere length. Tests for linear trend were performed by entering the ordinal exposure as continuous parameters in the models.
Results
There is an inverse association between telomere length and body mass index (BMI) (Ptrend = 0.005), waist circumference (Ptrend = 0.004), waist-to-height ratio (WHtR) (Ptrend = 0.004), weight (Ptrend = 0.010), and hip circumference (Ptrend = 0.026), but not waist-to-hip ratio (WHR) (Ptrend = 0.116) or height (Ptrend = 0.675). Weight change since age 50 was further evaluated among women over age 55. Women who maintained their weight within ±5% since age 50, particularly within a normal range (BMI = 18.5–24.9 kg/m2), or reduced their weight from overweight (BMI = 25–29.9 kg/m2) or obesity (BMI ≥30 kg/m2) to normal range, had a longer mean of current telomere length than women who gained weight since age 50 (Ptrend = 0.025), particularly those who stayed in obesity or gained weight from normal range or overweight to obesity (P = 0.023).
Conclusion
Our findings provide strong evidence supporting the hypothesis that telomere shortening is associated with obesity and that maintaining body weight within a normal range helps maintain telomere length.
doi:10.1002/oby.20321
PMCID: PMC3676725  PMID: 23408544
12.  Combination of uniform design with artificial neural network coupling genetic algorithm: an effective way to obtain high yield of biomass and algicidal compound of a novel HABs control actinomycete 
Controlling harmful algae blooms (HABs) using microbial algicides is cheap, efficient and environmental-friendly. However, obtaining high yield of algicidal microbes to meet the need of field test is still a big challenge since qualitative and quantitative analysis of algicidal compounds is difficult. In this study, we developed a protocol to increase the yield of both biomass and algicidal compound present in a novel algicidal actinomycete Streptomyces alboflavus RPS, which kills Phaeocystis globosa. To overcome the problem in algicidal compound quantification, we chose algicidal ratio as the index and used artificial neural network to fit the data, which was appropriate for this nonlinear situation. In this protocol, we firstly determined five main influencing factors through single factor experiments and generated the multifactorial experimental groups with a U15(155) uniform-design-table. Then, we used the traditional quadratic polynomial stepwise regression model and an accurate, fully optimized BP-neural network to simulate the fermentation. Optimized with genetic algorithm and verified using experiments, we successfully increased the algicidal ratio of the fermentation broth by 16.90% and the dry mycelial weight by 69.27%. These results suggested that this newly developed approach is a viable and easy way to optimize the fermentation conditions for algicidal microorganisms.
doi:10.1186/1475-2859-13-75
PMCID: PMC4051378  PMID: 24886410
Novel algicidal actinomycete; Uniform design; Artificial neural network coupling genetic algorithm; High yield of biomass and algicidal compound; HABs control
13.  Common genetic variants in the microRNA biogenesis pathway are not associated with breast cancer risk in Asian women 
Background
Although the role of microRNA in cancer development and progression has been well established, the association between genetic variants in microRNA biogenesis pathway genes and breast cancer risk has been yet unclear.
Methods
We analyzed data from two genome-wide association studies conducted in East Asian women including 5,066 cases and 4,337 controls. Among the SNPs which were directly genotyped or imputed, we selected 237 SNPs in 32 genes involved in microRNA biogenesis pathway and its regulation.
Results
Although 8 SNPs were nominally associated with breast cancer risk in combined samples (P<0.05), none of them were significant after adjustment for multiple comparisons.
Conclusions
The common genetic variants in microRNA biogenesis pathway genes may not be associated with breast cancer risk.
Impact
This study suggests no association between the polymorphisms in microRNA biogenesis pathway genes and breast cancer risk. Studies with large sample size and more genetic variants should be warranted to adequately evaluate the potential association.
doi:10.1158/1055-9965.EPI-12-0600
PMCID: PMC4030374  PMID: 22714736
breast cancer; genetic susceptibility; microRNA biogenesis pathway; single nucleotide polymorphism
14.  Quad-PRE: A Hybrid Method to Predict Protein Quaternary Structure Attributes 
The protein quaternary structure is very important to the biological process. Predicting their attributes is an essential task in computational biology for the advancement of the proteomics. However, the existing methods did not consider sufficient properties of amino acid. To end this, we proposed a hybrid method Quad-PRE to predict protein quaternary structure attributes using the properties of amino acid, predicted secondary structure, predicted relative solvent accessibility, and position-specific scoring matrix profiles and motifs. Empirical evaluation on independent dataset shows that Quad-PRE achieved higher overall accuracy 81.7%, especially higher accuracy 92.8%, 93.3%, and 90.6% on discrimination for trimer, hexamer, and octamer, respectively. Our model also reveals that six features sets are all important to the prediction, and a hybrid method is an optimal strategy by now. The results indicate that the proposed method can classify protein quaternary structure attributes effectively.
doi:10.1155/2014/715494
PMCID: PMC4052169  PMID: 24963340
15.  Low Body Mass Index and Blood Loss in Primary Total Hip Arthroplasty: Results from 236 Consecutive Ankylosing Spondylitis Patients 
BioMed Research International  2014;2014:742393.
Objective. To evaluate the effect of low body mass index (BMI) on blood loss during primary total hip arthroplasty (THA) in ankylosing spondylitis (AS) patients. Methods. Two hundred seventy-seven consecutive AS patients who underwent primary THA were retrospectively studied. The patients were divided by BMI into an underweight group (BMI < 18.5 kg/m2) and a normal weight group (18.5 kg/m2 < BMI < 25 kg/m2). Demographics, perioperative laboratory values, intraoperative data, blood loss, transfusion rate, transfusion reactions, surgical complications, hospitalization cost, and length of stay (LOS) were collected and analyzed. Results. Of 277 AS patients, 236 were eligible for inclusion in the study. A total of 91 (39%) patients were underweight. The hidden blood loss, transfusion rate, transfusion reactions, and hospitalization cost in the underweight group were significantly higher than those in the normal weight group. Conclusions. For AS patients, BMI appears to be correlated with blood loss during primary THA. Compared with patients of normal weight, low BMI patients have the potential to suffer more postoperative hidden blood loss and to require a higher transfusion rate.
doi:10.1155/2014/742393
PMCID: PMC4052846  PMID: 24959587
16.  Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects 
Nucleic Acids Research  2014;42(10):6591-6602.
Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disorder resulting from expression of RNA containing an expanded CUG repeat (CUGexp). The pathogenic RNA is retained in nuclear foci. Poly-(CUG) binding proteins in the Muscleblind-like (MBNL) family are sequestered in foci, causing misregulated alternative splicing of specific pre-mRNAs. Inhibitors of MBNL1-CUGexp binding have been shown to restore splicing regulation and correct phenotypes in DM1 models. We therefore conducted a high-throughput screen to identify novel inhibitors of MBNL1-(CUG)12 binding. The most active compound was lomofungin, a natural antimicrobial agent. We found that lomofungin undergoes spontaneous dimerization in DMSO, producing dilomofungin, whose inhibition of MBNL1–(CUG)12 binding was 17-fold more potent than lomofungin itself. However, while dilomofungin displayed the desired binding characteristics in vitro, when applied to cells it produced a large increase of CUGexp RNA in nuclear foci, owing to reduced turnover of the CUGexp transcript. By comparison, the monomer did not induce CUGexp accumulation in cells and was more effective at rescuing a CUGexp-induced splicing defect. These results support the feasibility of high-throughput screens to identify compounds targeting toxic RNA, but also demonstrate that ligands for repetitive sequences may have unexpected effects on RNA decay.
doi:10.1093/nar/gku275
PMCID: PMC4041448  PMID: 24799433
17.  1α, 25-Dihydroxyvitamin D Regulates Hypoxia-Inducible Factor-1α in Untransformed and Harvey-ras Transfected Breast Epithelial Cells 
Cancer letters  2010;298(2):159-166.
The purpose of this study was to determine the mechanism by which 1α, 25-dihydroxyvitamin D (1,25(OH)2D) alters hypoxia inducible factor-1α (HIF-1α) protein in untransformed and Harvey-ras (H-ras) oncogene transfected MCF10A breast epithelial cells. Treatment with1,25(OH)2D (10 nM) increased both mRNA (2.55±0.6 fold vs. vehicle, p=0.03) and protein levels (2.37±0.3 fold vs. vehicle, p<0.0001) of HIF-1α in MCF10A cells in 12 hours, which remained elevated at 24 hours. However, in H-ras transfected MCF10A cells, 1,25(OH)2D treatment increased HIF-1α protein level (2.08±0.38 fold vs. vehicle, p= 0.05) at 12 hrs, with no change in mRNA level and HIF-1α protein level returned to baseline after 24 hours. A transcription inhibitor prevented the 1,25(OH)2D induction of HIF-1α protein and mRNA levels in MCF10A cells, but failed to alter the induction of HIF-1α protein level in H-ras transfected MCF10A cells. On the other hand, inhibition of proteasomal degradation prevented the 1,25(OH)2D-induced HIF-1α protein level in H-ras transfected MCF10A but not in MCF10A cells. These results support that 1,25(OH)2D regulates HIF-1α protein level via transcriptional regulation in MCF10A cells in contrast to through proteosomal degradation with the presence of H-ras oncogene in MCF10A cells.
doi:10.1016/j.canlet.2010.06.014
PMCID: PMC4007490  PMID: 20655141
1,25-Dihydroxyvitamin D; 25-hydroxyvitamin D; Hypoxia-inducible factor; ras; Vitamin D Receptor
18.  Association between Body-Mass Index and Risk of Death in More Than 1 Million Asians 
The New England journal of medicine  2011;364(8):719-729.
Background
Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin.
Methods
We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors.
Results
In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range — by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI.
Conclusions
Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis.
doi:10.1056/NEJMoa1010679
PMCID: PMC4008249  PMID: 21345101
19.  Comorbidities and breast cancer survival: a report from the Shanghai Breast Cancer Survival Study 
BACKGROUND
We investigated the association of major comorbidities with breast cancer outcomes using the Shanghai Breast Cancer Survival Study, a population-based, prospective cohort study of Chinese women diagnosed with breast cancer.
METHODS
Analyses included 4,664 women diagnosed with stage I-III incident breast cancer aged 20–75 years (median age=51) during 2002–2006. Women were interviewed at 3–11 months post-diagnosis (median=6.4) and followed up by in-person interviews and linkage with the vital statistics registry. Multivariable hazard ratios (HRs) and (95% confidence intervals (CIs)) for the associations of comorbidities with breast cancer outcomes were estimated using Cox regression models.
RESULTS
After a median follow-up of 5.3 years (range: 0.64–8.9), 647 women died (516 from breast cancer) and 632 recurrence/metastases were documented. The main comorbidities reported included: hypertension (22.4%), chronic gastritis (14.3%), diabetes mellitus (6.2%), chronic bronchitis/asthma (5.8%), coronary heart disease (5.0%), and stroke (2.2). Diabetes was associated with increased risk of total mortality (adjusted HR: 1.40 (1.06–1.85)) and non-breast cancer mortality (adjusted HR: 2.64 (1.63–4.27)), but not breast cancer-specific mortality (adjusted HR: 0.98 (0.68–1.41)), adjusting for socio-demographics, clinical characteristics, selected lifestyle factors, and other comorbidities. Women with a history of stroke had a non-significant increased risk of total mortality (adjusted HR: 1.42 (0.91–2.22)) and a significant increased risk of non-breast cancer mortality (adjusted HR: 2.52 (1.33–4.78)), but not breast cancer-specific mortality (adjusted HR: 0.78 (0.38–1.62)). Overall, none of the comorbidities investigated were significantly associated with recurrence.
CONCLUSIONS
In this large prospective cohort of breast cancer survivors, diabetes was significantly associated with increased risk of total and non-breast cancer mortality, and history of stroke was associated was associated with increased risk of non-breast cancer mortality.
doi:10.1007/s10549-013-2521-2
PMCID: PMC3712758  PMID: 23605082
breast cancer; prognosis; survival; comorbidity
20.  Relationship Between Changes in Brain MRI and 1H-MRS, Severity of Chronic Liver Damage, and Recovery After Liver Transplantation 
Magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (1H-MRS) have been used in clinics for diagnosis of chronic liver diseases. This study was designed to investigate the relationship between MRI/MRS outcomes and the severity of liver damage. Of 50 patients examined, the MRI signal intensity in the globus pallidus as determined by pallidus index (PI) increased as the disease severity (scored by Child Pugh ranking) worsened (r = 0.353, P < 0.05). The changes in PI values were also linearly associated with Mn concentrations in whole blood (MnB) (r = 0.814, P < 0.01). MRS analysis of four major brain metabolites (i.e., Cho, mI, Glx, and NAA) revealed that the ratios of Cho/Cr and mI/Cr in cirrhosis and CHE patients were significantly decreased in comparison to controls (P < 0.05), whereas the ratio of Glx/Cr was significantly increased (P < 0.05). The Child Pugh scores significantly correlated with mI/ Cr (−0.484, P < 0.01) and Glx (0.369, P < 0.05), as well as MnB (0.368, P < 0.05), but not with other brain metabolites. Three patients who received a liver transplant experienced normalization of brain metabolites within 3 months of post-transplantation; the MR imaging of Mn in the globus pallidus completely disappeared 5 months after the surgery. Taken together, this clinical study, which combined MRI/MRS analysis, autopsy exam and liver transplant, clearly demonstrates that liver injury-induced brain Mn accumulation can reversibly alter the homeostasis of brain metabolites Cho, mI and Glx. Our data further suggest that liver transplantation can restore normal brain Mn levels.
doi:10.3181/0903-RM-118
PMCID: PMC4005269  PMID: 19546351
hepatic encephalopathy; magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS); Child Pugh; manganese; choline; glutamine; liver transplant
21.  Alteration of Serum Concentrations of Manganese, Iron, Ferritin, and Transferrin Receptor Following Exposure to Welding Fumes Among Career Welders 
Neurotoxicology  2005;26(2):257-265.
This study was performed to determine airborne manganese levels during welding practice and to establish the relationship between long-term, low-level exposure to manganese and altered serum concentrations of manganese, iron, and proteins associated with iron metabolism in career welders. Ninety-seven welders (average age of 36 years) who have engaged in electric arc weld in a vehicle manufacturer were recruited as the exposed group. Welders worked 7–8 h per day with employment duration of 1–33 years. Control subjects consisted of 91 employees (average age of 35 years) in the same factory but not in the welding profession. Ambient manganese levels in welders’ breathing zone were the highest inside the vehicle (1.5 ± 0.7 mg/m3), and the lowest in the center of the workshop (0.2 ± 0.05 mg/m3). Since the filter size was 0.8 μm, it is possible that these values may be likely an underestimation of the true manganese levels. Serum levels of manganese and iron in welders were about three-fold (p < 0.01) and 1.2-fold (p < 0.01), respectively, higher than those of controls. Serum concentrations of ferritin and transferrin were increased among welders, while serum transferrin receptor levels were significantly decreased in comparison to controls. Linear regression analyses revealed a lack of association between serum levels of manganese and iron. However, serum concentrations of iron and ferritin were positively associated with years of welder experience (p < 0.05). Moreover, serum transferrin receptor levels were inversely associated with serum manganese concentrations (p < 0.05). These findings suggest that exposure to welding fume among welders disturbs serum homeostasis of manganese, iron, and the proteins associated with iron metabolism. Serum manganese may serve as a reasonable biomarker for assessment of recent exposure to airborne manganese.
doi:10.1016/j.neuro.2004.09.001
PMCID: PMC4002285  PMID: 15713346
Manganese; Iron; Ferritin; Transferrin; Transferrin receptor; Welder; Welding fume; Biomarker; Airborne manganese
22.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
23.  Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women 
Journal of Clinical Oncology  2013;31(12):1548-1553.
Purpose
We recently reported an inverse association between soy food intake and lung cancer risk among nonsmoking women. The effect size for aggressive lung cancers was larger than that observed for other types of lung cancer. Therefore, we hypothesized that soy consumption may favorably affect the overall survival of patients with lung cancer.
Patients and Methods
This analysis included 444 women with incident lung cancer identified from the Shanghai Women's Health Study. Prediagnosis soy food intake was assessed at enrollment and reassessed 2 years later. Proportional hazards models were used to evaluate the association between soy food intake and overall survival.
Results
Of the 444 patients with lung cancer, 318 died during follow-up. Initial analyses including all patients showed that higher intake of soy food was associated with better overall survival after adjusting for demographic and lifestyle characteristics and other nonclinical factors. Larger effect sizes for the association were found after additional adjustment for tumor stage and treatment in analyses including 301 patients with data available on these clinical factors. Compared with the median intake of soy food, fully adjusted hazard ratios for total mortality associated with the 10th, 30th, 70th, and 90th percentiles of intake were 1.81 (95% CI, 1.26 to 2.59), 1.25 (95% CI, 1.09 to 1.42), 0.88 (95% CI, 0.80 to 0.97), and 0.89 (95% CI, 0.68 to 1.16), respectively. Similar inverse associations were observed for dietary isoflavone intake.
Conclusion
This study suggests, to the best of our knowledge for the first time, that, among women with lung cancer, prediagnosis intake of soy food is associated with better overall survival.
doi:10.1200/JCO.2012.43.0942
PMCID: PMC3625711  PMID: 23530109
24.  A Common Deletion in the APOBEC3 Genes and Breast Cancer Risk 
Background
Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.
Methods
We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.
Results
Of the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10−4) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10−22). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10−24).
Conclusions
We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
doi:10.1093/jnci/djt018
PMCID: PMC3627644  PMID: 23411593
25.  An Alternative Direct Compound Dispensing Method Using the HP D300 Digital Dispenser 
Journal of laboratory automation  2013;18(5):367-374.
Evaluation of compound activity in vitro is crucial to drug discovery efforts and require that the compounds be accurately and reliably titrated and dispensed to the assay wells. The HP D300 dispenser utilizes inkjet technology to achieve small volume dispensing that allows concentration response testing using the direct dilution paradigm. While inkjet technology has been long in existence, it is new to the field of screening and drug development. We have evaluated the D300 dispenser in a biochemical assay, a cell-based reporter gene assay and a cytotoxicity assay. The software for this instrument is user-friendly and the compound dispensing process is streamlined. However, a limitation is that this dispenser is currently only applicable to 96-well and 384-well plate formats, and not to 1536-well high density plates. Our results indicate that the D300 generates clean and reproducible results that correlate with those produced with more commonly used instruments such as the pin tool. We found that the instrument is useful and can improve the throughput of compound dispensing in 96-well and 384-well plates.
doi:10.1177/2211068213491094
PMCID: PMC3985129  PMID: 23708834
compound dispenser; liquid handler; compound screen; serial dilution; direct dilution

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